2-substituted-3a,4,5,6,7,7a-hexahydro-3a-hydroxybenzothiazolium halides

ABSTRACT

X(-)   9A-(HO-),5A,6,7,8,9,9A-HEXAHYDRO(2,1-B)BENZOTHIAZOLIUM   BENZOTHIAZOLIUM X(-) AND   9-(R1-O-CO-),9A-(HO-),5A,6,7,8,9,9A-HEXAHYDROPYRIDO(2,1-B)   HEXAHYDROBENZOTHIAZOLIUM X(-),   2-(R2-PHENYL),3-R3,3A-(HO-),4-(R1-O-CO-),3A,4,5,6,7,7A-   NOVEL PHARMACOLOGICALLY ACTIVE COMPOUNDS HAVE BEEN PREPARED OF THE FORMULAE- WHEREIN R1 AND R3 ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND (LOWER)ALKYL; R2 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, (LOWER)ALKYL, NITRO, HALOGEN, (LOWER)ALKOXY, HYDROXY AND R4-N(-R5)WHEREIN R4 AND R5 WHEN NOT CONCATENATED ARE INDEPENDENTLY SELECTED FROM THE GROUP CONSISTING OF PIPERAZINYL, PIPERIDI (LOWER)ALKYL AND WHEN CONCATENATEDFROM A RADICAL SELECTED FROM THE GROUP CONSISTING OF PIPERAZINLY, PIPERIDINYL, PYRROLIDINYL AND MORPHOLINYL; X IS HALOGEN.

United States Patent 3,823,153 Z-SUBSTITUTED-3a,4,5,6,7,7a-HEXAHYDRO-3a-HYDROXYBENZOTHIAZOLIUM HALIDES Peter H. L. Wei, Springfield, Pa.,assignor to American Home Products Corporation, New York, N.Y.

No Drawing. Original application Mar. 17, 1971, Ser. No. 125,410, nowPatent No. 3,694,449. Divided and this application May 15, 1972, Ser.No. 253,376

Int. Cl. C07d 91/24 US. Cl. 260306.7 2 Claims ABSTRACT OF THE DISCLOSURENovel pharmacologically active compounds have been prepared of theformulae s L 6 e x e 0H and wherein R and R are selected from the groupconsisting of hydrogen and (lower)alkyl; R is selected from the groupconsisting of hydrogen, (lower)alkyl, nitro, halogen, (lower) alkoxy,hydroxy and wherein R and R when not concatenated are independentlyselected from the group consisting of hydrogen and (lower)a1kyl and whenconcatenated form a radical selected from the group consisting ofpiperazinyl, piperidinyl, pyrrolidinyl and morpholinyl; X is halogen.

This is a division of application Ser. No. 125,410, filed Mar. 17, 1971,now US. Pat. 3,694,449, granted Sept. 26, 1972.

Description of the Invention This invention is concerned with thepreparation of novel chemical compounds which are pharmacologicallyactive as central nervous system depressants. They are useful as calmingagents for mammals.

The compounds are of the formulae:

Patented July 9, 1974 p we and

wherein R and R are hydrogen and (lower)alkyl; R is selected from thegroup consisting of hydrogen, (lower) alkyl, nitro, halogen,(lower)alkoxy, hydroxy and.

wherein R and R when not concatenated are independently selected fromthe group consisting of hydrogen and (lower)alkyl and when concatenatedform a radical selected from the group consisting of piperazinyl,piperidinyl, pyrrolidinyl and morpholinyl; X is halogen.

The compounds of Formula I may be prepared according to the followingreaction scheme:

wherein R R and X are the same as hereinabove defined and R is loweralkyl.

The compounds are prepared by heating the reaction in an alcoholsolution at a temperature of to for a period of 3 to 8 hours. Thesolvent is removed and the residue is triturated with ether anddimethoxyethane and the crude solid material which is collected can bere crystallized from ethanol.

Compounds of Formula Il may be prepared by the folwherein X is the sameas hereinabove defined and R is lower alkyl. The reactants are allowedto react in glacial acetic acid at a temperature of from 80 to 100 for aperiod of 2 to hours. Upon cooling, the solid is collected and washedwith dimethoxyethane and ether. The crude material can be recrystallizedfrom ethanol.

Compounds of Formula I and Formula II wherein R is hydrogen may beprepared by the hydrolysis of the corresponding ester. The preferredmethod of hydrolysis is to use a 4050% mixture hydrohalic acid such ashydrobromic acid at a temperature of from -50 to 80 for a period of 20to 40 minutes. After the solvent is removed at reduced pressure, theresidue may be triturated with a solvent, such as acetone and collected.

As used herein the term (lower)alkyl is used to include hydrocarbonradicals such as methyl, ethyl, n-propyl, i-propyl and n-butyl. The termhalogen is used to include chlorine, bromine and iodine.

In the evaluation of the biological activity of the compounds of thisinvention, the in vivo effects were tested as follows: The compound wasadministered orally or intraperitoneally to three mice (14 to 24 grams)at each of the following doses: 400, 127, 40 and 12.7 milligrams perkilogram of host body Weight (MPK). The animals were watched for aminimum of two hours during which time signs of general stimulation,(i.e., increased spontaneous motor activity, hyperactivity on tactilestimulation, twitching), general depression (i.e., decreased spontaneousmotor activity, decreased respiration), autonomic activity (i.e.,miosis, mydriasis, diarrhea) were noted.

The compounds of this invention induce central nervous system depressanteffects at a dose of 127 to 400 MPK. Thus the compounds of theinvention, have demonstrated utility as pharmacologically activecompounds in experimental and comparative pharmacology and are of valuein the treatment of mammals, e.g., mice, rats, etc., who are responsiveto treatment with central nervous system depressant agents. Specificallythe compounds may be administered for the purpose of inducing a calmingeffect in mammals.

,When the compounds of the invention are employed as described above,they may be administered alone or in combination with pharmacologicallyacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmacological practice. For example, theymay be administered orally in the form of tablets or capsules containingsuch excipients as starch, milk sugar, calcium carbonate and the like.They may be administered orally in the form of solutions which maycontain coloring and flavoring agents or they may be administered byparenteral injection, e.g., intramuscular injection. The injectablesolution may contain other solutes such as sodium chloride or glucose ina suificient quantity to render the solution isotonic.

The dosage of the pharmacological agents of the invention may vary withthe route of administration and the particular compound chosen.

The following examples are not to be construed as limitations of theinvention:

EXAMPLE 1 4-Carboxy 2 (p-dimethylaminophenyl)-3a,4,5,6,7,7a-

hexahydro 3a hydroxy 3 methylbenzothiazolium bromide ethyl esterp-Dimethylamino N methylthiobenzamide was prepared following theprocedure of Gaomaise and Chambers. [J. Med. Chem. 11, 1205-8 (1968)]. 1

An alcoholic solution of 6-bromo-2-carbethoxycyclohexanone (4.9 g., 0.02m.) and p-dimethylamino-N-methylthiobenzamide (3.6 g., 0.02 m.) washeated to reflux for 5 hours. After removal of ethanol the residue wastreated with ether. The residue upon standing solidified. The crudematerial after treatment with dimethoxy ethane weighed 5.0 g. and meltedat 8 C. Recrystallization from ethanol gave pure ethyl ester of4-carboxy-2-(p-dimethylaminophenyl)-3a,4,5,6,7,7a-hexahydro 3ahydroxy-3- methylbenzothiazolium bromide, m.p. 181-3 C.

Analysis.-Calcd. for C19H27BI'N2O3SZ C, 51.46; H, 6.14; N, 6.32. Found:C, 51.26; H, 6.09; N, 6.30. IR(KBr): 3.4a (OH); 5.8 (ester CO); 6.25(C=N). NMR (CDCl;,): 67.3 (m, 4); 4.3 (q 2, OCH 1.3 (t, 3, CH NCH 3.2(s, 3); 3.7 (m).

EXAMPLE 2 9-Carboxy-5a,6,7,8,9,9a-hexahydro-9a-hydroxypyrido-[l,2-b]benzothiazolium bromide, ethyl ester An acetic acid (60 ml.)solution of 6-bromo-2-carbethoxycyclohexanone (12.45 g. or 0.05 m.) andZ-mercaptopyridine (5.55 g. or 0.05 m.) was heated on a steam bath for3% hours. Upon cooling the solid that separated was collected and washedwith dimethoxyethane and ether. The crude material was recrystallizedfrom ethanol. The pure ethyl ester of9-carboxy-5a,6,7,8,9,9a-hexahydro-9a hydroxypyrido[2,1bJbenzd-thiazolium bromide weighed 14.9 g., (82% yield), m.p. 206207.

Analysis.Calcd. for C H NO S-Br: C, 46.67; H, 5.03; Br, 22.18; N, 3.89;S, 8.90. Found: C, 46.48; H, 4.97; Br, 22.07; N, 4.03; S, 8.70. IRspectrum (KBr) showed the presence of ester absorption at 5.8 and theabsence of keto carbonyl at 6.0;/.. NMR spectrum (DMSOd 61.1 (t, J =7Hz.) 4.1 (q, J =7 Hz.). Other aliphatic protons as complex multipletsabsorbed at 1.8 to 2.2 and 3.a, the hydroxy proton was found at 64.8 wasexchanged in D 0.

EXAMPLE 3 5a,6,7,8,9,9a-Hexahydro-9a-hydroxypyrido-[2,1-b]benzothiazolium bromide A 48% HBr (30 ml.) solution of ethylester 9-carboxy- 5a-6,7,8,9,9a-hexahydro 9a hydroxypyrido[2,lb]benzothiazolium bromide (6.0 g.) was heated on a steam bath. Gasevolution ceased at the end of the reaction period (3 hours). Thesolvent was removed in vacuo and the residue treated with benzene andthe benzene was also removed. The resdue was finally treated withacetone and the solid collected which weighed 4.4 g. Uponrecrystallization from ethanol pure5a,6,7,8,9,9a-heXahydro-9a-hydroxypyrido[2,1-b]benzothiazolium bromidemelted at 213- 5 C.

Analysis.-Calcd. for C H NOS-Br: C, 45.83; H, 4.90; Br, 27.73; N, 4.86;S, 11.13. Found: C, 45.66; H, 5.09; Br, 27.40; N, 4.98; S, 11.16. IRspectrum (KBr) showed the disappearance of carbonyl absorption. NMR(DMSOd 68.5 (m); 4.6 (t); complex multiplet 1.86.

By analogous methods the chlorine and iodide salts may be obtained.

EXAMPLE 4 9-Carboxy-5a,6,7,8,9,9'a-hexahydro-9a-hydroxypyrido[2,1-b1benzothiazolium bromide 4.46; Br, 23.77; N, 4.26; S, 9.83. IR(KBr) 3.5,u (OH); 5.85 (carboxyl CO). NMR (DMSMe) 68.5 (m); aliphatic,1.9 (m) By methods analogous to those employed in Example 1, thefollowing compounds are prepared:

TABLE I 4carboxy-2- (p-nitrophenyl) -3 a,4,5 ,6,7,7a-hexahydro-3ahydroxy-3-ethylbenzothiazolium bromide, methyl ester 4-car boxy-2-(p-toluene) 3 a-4,5 ,6,7 ,7 a-hexahydro-3ahydroxy-3-methylbenzothiazolium chloride, n-propyl ester 4-carboxy-2-(p-bromophenyD-B a-4,5,6,7,7a-hexahydro-3a-hydroxy-3-methylbenzothiazolium bromide, ethyl ester4-carboXyl-2-(p-ethoxyphenyD-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-n-propylbenzothiazo1ium bromide,ethyl ester 4-carb oxy-2- m-chlorophenyl) -3 a,4,5,6,7,7a-hex ahydro-3a-hydroxy-3-ethylbenzothiazolium bromide, methyl ester4-carboxy-2-(p-ethylphenyl)-3a,4,5,6,7,7a-hexahydro-3ahydroxy-3-n-propyl-benzothiazoliumbromide, i-propyl ester 4-carboxy-2-(p-hydroxyphenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-methylbenzothiazolium chloride, ethyl ester4-car'boxy-2-(p-methoxyphenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide, methyl ester 4-carboxy-2-[p-4-morpholinyl) phenyl] -3a,4,5,6,7,7ahexahydro-3a-hydroxy-3-methylbenzothiazolium bromide, ethylester 4-carboxy-2- [pl-piperidinyl) phenyl]-3a,4,5,6,7,7a-

hexahydro-3a-hydroxy-3-methylbenzothiazolium chloride, methyl ester4-carboxy-2- (p-aminophenyl)-3 a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide, ethyl ester4-carboxyr2-phenyl-3a,4,5,6,7,7a-hexahydro-3 ahydroxy-S-methylbenzothiazolium chloride, isopropyl ester 4-carboxy-2- [p-(N-methylamino) phenyl] -3a,4,5,6,7,7a-

hexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide, n-propyl ester4-carboxy-2- [p-( l-piperazinyl )phenyl] -3a,4,5,6,7,7ahexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide, methylester 4-carboxy-2- [p-( 1-pyrrolidinyl)phenyl]-3a,4,5,6,7,7ahexahydro-3a-hydroxy-3-methylbenzothiazolium fluoride,ethyl ester By methods analogous to those employed in Example 4 thefollowing compounds may be obtained:

TABLE II4-carboxy-2-(p-nitrophenyl)-3a,4,5,6,7,7a-hexahydro-3ahydroxy-3-ethylbenzothiazoliumbromide 4-carboxy-2-(p-toluene)-3a,4,5,6,7,7a-hexahydro-3ahydroxy-3-methylbenzothiazoliumchloride 4-carboxy-2- (p-bromophenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-methylbenzothiazolium bromide4-carboxy-2-(p-ethoxyphenyl)-3 a,4,5,6,7,7a-hexahydro-3a-hydroxy-S-n-propylbenzothiazolium bromide4-carboxy-2-(m-chlorophenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-3-ethylbenzothiazolium bromide4-carboxy-2-(p-ethylphenyl)-3a,4,5,6,7,7a-hexahydro-3a-hydroxy-B-n-propylbenzothiazolium bromide TABLE IIC0ntinued Iclaim: 1. A compound selected from the group consisting of wherein R andR are selected from the group consisting of hydrogen and alkyl of up tofour carbon atoms; R; is selected from the group consisting of hydrogen,alkyl of up to four carbon atoms, nitro, chlorine, bromine, iodine,alkoxy of up to four carbon atoms, hydroxy and wherein R and R when notconcatenated are independently selected from the group consisting ofhydrogen and alkyl of up to four carbon atoms and when concatenated forma radical selected from the group consisting of piperazinyl,piperidinyl, pyrrolidinyl and morpholinyl; X is halogen.

2. A compound as defined in claim 1 which is4-carboxyl-Z-(p-dimethylaminophenyl)-3a,4,5,6,7,7a hexahydro3ahydroxy-3-methylbenzothiazolium bromide, ethyl ester.

References Cited UNITED STATES PATENTS 3,694,449 9/1972 Wei 260-3061RICHARD J. GALLAGHER, Primary Examiner US. Cl. X.R.

